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Role of Lentiviral Restriction Factors in Resistance to SIV Infection In Vivo

Aamer, Hadega/A (2013) Role of Lentiviral Restriction Factors in Resistance to SIV Infection In Vivo. Master's Thesis, University of Pittsburgh. (Unpublished)

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Abstract

Lentiviral restriction factors (RFs) are cellular proteins potently capable of blocking virus replication in vitro and delaying disease progression in vivo. Currently, five RFs (APOBEC3G, TRIM5α, Tetherin, SAMHD1, and Schlafen 11) are considered part of the intrinsic immune response to viral infection for their ability to block virus replication prior to activation of the innate immune system. Although RFs are constitutively expressed, it is unknown whether basal and early induction levels of these RFs are capable of limiting virus dissemination following mucosal challenge. We hypothesize that higher basal RF levels can exert a protective effect by delaying systemic infection. Real-time PCR analysis was conducted to analyze basal and post-exposure RF expression in the blood, lymph nodes and duodenum. Eight Indian-origin rhesus macaques received repetitive low dose rectal exposures of SIV/DeltaB670: 3 macaques became infected after 2 challenges (susceptible), 2 became infected after 3 challenges (intermediate), while two became infected after 6 challenges (resistant). One animal remained persistently uninfected despite 7 challenges (elite controller). Analysis of basal RF and Mx1 expression in the blood revealed animals resistant to infection had significantly higher TRIM5α and Mx1 expression than susceptible animals. Longitudinal analysis of RF and Mx1 expression in the blood revealed no RF induction in the resistant group, while the susceptible and intermediate groups experienced a 2 to 7-fold induction after virus appearance in the blood. Despite the lack of RF induction in the elite controller, a transient induction of Mx1 was evident after 2 of the 7 challenges, which may have provided further protection. Examination of RF induction in the gut revealed a similar pattern with expression mirroring that seen in the blood. Our results suggest that RFs are coordinately expressed in the blood and gut in response to infection and that levels remain unchanged, despite repeated exposure, until the animals become viremic. As such, induction of these RFs after virus exposure appears to be insufficient in containing virus dissemination. These results further suggest that basal RF levels in the blood may be used as a predictor for susceptibility to infection in macaques and possibly humans.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Aamer, Hadega/Ahaa44@pitt.eduHAA44
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairMurphey-Corb, Michaelmcorb@pitt.eduMCORB
Committee MemberReinhart, Todd A.reinhar@pitt.eduREINHAR
Committee MemberNorris, Karen Akan1@pitt.eduKAN1
Date: 30 August 2013
Date Type: Publication
Defense Date: 19 August 2013
Approval Date: 30 August 2013
Submission Date: 29 August 2013
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
Number of Pages: 125
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Molecular Virology and Microbiology
Degree: MS - Master of Science
Thesis Type: Master's Thesis
Refereed: Yes
Uncontrolled Keywords: HIV,SIV,AIDS,Restriction factor,APOBEC3G,TRIM5,Tetherin,SAMHD1,Schlafen 11,mucosa,rectal,low dose,repetitive,rhesus macaque,resistance,susceptible,gut,duodenum,lymph node,innate immunity,adaptive immunity,Mx1,IFN,lentivirus,sexual transmission,low dose,mRNA,RT-PCR
Date Deposited: 30 Aug 2013 14:23
Last Modified: 30 Aug 2018 05:15
URI: http://d-scholarship.pitt.edu/id/eprint/19736

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